The complex cancer genetics and the multiple pathways operational in cancer motivate the fundamental hypothesis of this Program: Combination therapies that are mechanistically complementary and directed at non-overlapping molecular targets and pathways will significantly advance cancer treatment outcomes. The current, heavily revised application builds on our own findings, recent advances in the understanding of cancer biology and mechanisms and the progress in imaging technologies, to propose new photodynamic therapy (PDT)-based combination treatments for pancreatic cancer (PanCa) and non-melanoma skin cancers (NMSC). PDT is a photochemistry-based modality that is approved for the treatment of a number of cancer and non-cancer pathologies. Strategically, combinations will be selected such that the first treatment enhances the second. This is achieved by: (i) preconditioning tumors with agents that initiate molecular events that augment PDT and (ii) administering a second treatment specifically tailored to a particular molecular response elicited by the first. This second approach is strengthened by our new nanoconstructs (NCs) capable of simultaneous multi-inhibitor delivery. PDT is a standard component of the combination, while the second modality can be small molecule enhancers, chemo or biologic therapeutics. The choice of the specific combination reagent will be heavily influenced by the likelihood of rapid translation to the clinic in Projects 1 and 2. Toward this gol, we have recruited pharmaceutical industries that are already running clinical trials with reagents that may potentially synergize with PDT. Optical imaging will provide online monitoring of light and photosensitizer dosimetry, treatment planning and molecular response. The Program has 4 projects supported by 3 Cores. Project 1 investigates molecular pathways of small molecules that enhance ALA-PDT to increase therapy response in skin carcinomas in humans. Project 2 uses PDT and combinations ('first in human) to address metastasis in addition to local control by PDT and thus advance the survival and quality of life of patients with PanCa and precancer. Project 3 develops NCs combinations in preclinical models (3D in vitro, orthotopic and genetically engineered mice) to steer clinical studies in Project 2 within the current cycle and, i a more forward looking approach develops targeted multi-inhibitor NCs. Project 4 develops quantitative tools to monitor molecular features of tumor treatment response for integrated dosimetry for standard clinical procedures. Cores provide administration, education, models, instrumentation and technology transfer. Impact: This program positively impacts on the treatment and prevention of two cancers: decreasing mortality and morbidity in PanCa with few therapy options and NMSC with many treatment options but a high incidence, thus putting a heavy societal burden of cost and suffering. These findings could also be translated to other cancers. Scientifically, the tools developed (models, imaging and nanotechnology) provide a platform for the evaluation of new therapeutics and mechanisms.